OsK1 is a 38-residue peptide with 3 disulphide bridges and is found in the venom of the scorpion Orthochirus scrobiculosus. It is one of a number of short chain scorpion toxins which contain between 29 and 39 amino acid residues, are crosslinked by 3 or 4 disulphide bridges and are active on several potassium channel subtypes, both voltage gated and calcium activated. These short chain scorpion toxins have been classified by Tytgat et al., Trends Pharmacol. Sci., 20(11), 444-447, 1999. OsK1 is a group 3 toxin and is shown below in Table 1 along with the other group 3 toxins and one group 6 toxin, Maurotoxin (MTx).
TABLE 13.1 KTxGVEINVKCSGSPQCLKPCKDA-GMR-FGKCMNR-KCHCTPK 3.2 AgTx2GVPINVSCTGSPQCIKPCKDA-GMR-FGKCMNR-KCHCTPK 3.3 AgTx3GVPINVPCTGSPQCIKPCKDA-GMR-FGKCMNR-KCHCTPK 3.4 AgTx1GVPINVKCTGSPQCLKPCKDA-GMR-FGKCING-KCHCTPK 3.5 KTx2VRIPVSCKHSGQCLKPCKDA-GMR-FGKCMNR-KCDCTPK 3.6 BmKTxVGINVKCKHSGQCLKPCKDA-GMR-FGKCING-KCDCTPK 3.7 OsK1GVIINVKCKISRQCLEPCKKA-GMR-FGKCMNG-KCHCTPK 3.8 Bs6GVPINVKCRGSPQCIQPCRDA-GMR-FGKCMNG-KCHCTPQ 6.2 MTxVSCTGSKDCYAPCRKQTGCPNA-KCINK-SCKCYGC
Both the mammalian voltage-gated K+ channel Kv1.3 and the type 1 intermediate-conductance Ca2+-activated channel KCa3.1 (also referred to as IK1) are expressed in immune T-cells. Their relative abundance at the T-cell surface depends on the state of lymphocyte activation and differentiation. The potassium channel phenotype varies during the progression from the resting to the activated T-cell state, and from naive to effector memory T-cells. Therefore, blockers of these channel types possess potent immunomodulatory properties that could be beneficial in the treatment of human diseases, such as multiple sclerosis. Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system, characterised by progressive demyelination and axonal damage caused by reactive autoimmune lymphocytes. Activation and proliferation of these cells (effector memory T-cells) relies upon Kv1.3 channels (and possibly IK1 channels), and can be blocked by Kv1.3 channel blockers. Demyelination also involves unmasking of the Kv1.1 and Kv1.2 subtypes, which provokes leak currents and a decrease in nervous transmission (by altering the action potential).
We have found that OsK1, alone amongst the short chain scorpion toxins, is potently active on Kv1.1, Kv1.2 and Kv1.3 channels, and moderately active on IK1. It would be desirable to find synthetic peptides which retain or enhance this property- or part of this property- and/or block more potently the IK1 subtype.
Such derivatives may also be useful against other human disorders, such as graft rejection, rheumatoid arthritis, bone degradation, and cancer (abnormal cell proliferation).